Digital Commons Network^™

Registry-Based Cohort Study Of Alpha-1 Antitrypsin Deficiency Prevalence, Incidence And Mortality In Denmark 2000-2018, John Acquavella, Emese Vágó, Henrik Toft Sorensen, Erzsébet Horváth-Puhó, Gregory P. Hess

College of Population Health Faculty Papers

OBJECTIVE: To estimate the prevalence of diagnosed alpha-1 antitrypsin deficiency (dAATD) in Denmark as of 31 December 2018, and dAATD incidence and mortality from 1 January 2000 to 31 December 2018.

STUDY DESIGN AND SETTING: We used the Danish National Patient Registry to identify patients with dAATD based on the International Classification of Diseases, 10th Revision (ICD-10) code E88.0A and the Danish Civil Registration System (CRS) for population counts and vital status. We estimated dAATD prevalence, incidence and mortality. We compared mortality among patients with dAATD and an age-matched and sex-matched cohort extracted from the Danish CRS. We conducted a …

Stakeholder Perspectives On The Demand And Supply Factors Driving Substandard And Falsified Blood Pressure Lowering Medications In Nigeria: A Qualitative Study, Grace Shedul, Olutobi Adekunle Sanuade, Eugenia N Ugwuneji, Tunde M Ojo, Aishwarya Vijay, Patrick Ponzing, Inuwa Okpe, Gabriel Lamkur Shedul, Mark D Huffman, Dike Ojji, Lisa R Hirschhorn

2020-Current year OA Pubs

OBJECTIVES: Although substandard and falsified (SF) blood pressure (BP) lowering medications are a global problem, qualitative research exploring factors driving this in Nigeria has not been reported. This study provides information on factors driving demand for and supply of low-quality BP lowering medications in Nigeria and potential strategies to address these factors.

METHODS: This was a cross-sectional qualitative study. Between August 2020 and September 2020, we conducted 11 in-depth interviews and 7 focus group discussions with administrators of health facilities, major manufacturers and distributors of BP lowering medications, pharmacists, drug regulators, patients and primary care physicians purposively sampled from the …

Hif1a-Dependent Induction Of Alveolar Epithelial Pfkfb3 Dampens Acute Lung Injury, Eszter K Vladar, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during …

A Genome-Wide Association Study Of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants, Harold Bae, Ping An, Mary Feitosa, Et Al.

2020-Current year OA Pubs

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609,

Expanded Proteomic Survey Of The Human Parasite Leishmania Major Focusing On Changes In Null Mutants Of The Golgi Gdp-Mannose/Fucose/Arabinopyranose Transporter, Gloria Polanco, Nichollas E Scott, Lon F Lye, Stephen M Beverley

2020-Current year OA Pubs

The trypanosomatid protozoan parasite

Patient-Centered Outcomes Of An Emergency Department Social And Medical Resource Intervention, Daniela Ortiz, Karen Kurian, Thiago Halmer, Michael S Jaung

Faculty, Staff and Students Publications

INTRODUCTION: Few studies have examined the impact of emergency department (ED) social interventions on patient outcomes and revisits, especially in underserved populations. Our objective in this study was to characterize a volunteer initiative that provided community medical and social resources at ED discharge and its effect on ED revisit rates and adherence to follow-up appointments at a large, county hospital ED.

METHODS: We performed a cross-sectional analysis of ED patients who received medical and social resources and an educational intervention at discharge between September 2017-June 2018. Demographic information, the number of ED return visits, and outpatient follow-up appointment adherence within …

Large-Scale Crispri And Transcriptomics Of Staphylococcus Epidermidis Identify Genetic Factors Implicated In Lifestyle Versatility., Michelle Spoto, Johanna P. Riera Puma, Elizabeth Fleming, Changhui Guan, Yvette Ondouah Nzutchi, Dean Kim, Julia Oh

Faculty Research 2022

Staphylococcus epidermidis is a ubiquitous human commensal skin bacterium that is also one of the most prevalent nosocomial pathogens. The genetic factors underlying this remarkable lifestyle plasticity are incompletely understood, mainly due to the difficulties of genetic manipulation, precluding high-throughput functional profiling of this species. To probe the versatility of S. epidermidis to survive across a diversity of environmental conditions, we developed a large-scale CRISPR interference (CRISPRi) screen complemented by transcriptional profiling (RNA sequencing) across 24 diverse conditions and piloted a droplet-based CRISPRi approach to enhance throughput and sensitivity. We identified putative essential genes, importantly revealing amino acid metabolism as …

Progressive Acceleration Of Insulin Exposure Over 7 Days Of Infusion Set Wear, Jasmin R. Kastner, Timothy S. Bailey, Poul Strange, Leon Shi, Keith A. Oberg, Paul J. Strasma, Jeffrey I. Joseph, Douglas B. Muchmore

Department of Anesthesiology Faculty Papers

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report insulin pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide tmax (P < 0.001), Cmax (P < 0.05), and mean residence time (P < 0.0001). Area under the insulin concentration curve (AUC0–300) declined by ∼24% from days 0 to 7 (P < 0.05). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. The study was registered in clinicaltrials.gov (NCT04398030).

A Flexible-Hazards Cure Model With Application To Patients With Soft Tissue Sarcoma

Faculty, Staff and Student Publications

In medical research, it is often of great interest to have an accurate estimation of cure rates by different treatment options and for different patient groups. If the follow-up time is sufficiently long and the sample size is large, the proportion of cured patients will make the Kaplan-Meier estimator of survival function have a flat plateau at its tail, whose value indicates the overall cure rate. However, it may be difficult to estimate and compare the cure rates for all the subsets of interest in this way, due to the limit of sample sizes and curse of dimensionality. In the …

Correlations Between Complex Human Phenotypes Vary By Genetic Background, Gender, And Environment, Alanna C Morrison, Ani W Manichaikul, Xiuqing Guo, Nora Franceschini, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Donald M Lloyd-Jones, Myriam Fornage, Adolfo Correa, Nancy L Heard-Costa, Ramachandran S Vasan, Ryan Hernandez, Robert C Kaplan, Susan Redline, Tamar Sofer

Faculty, Staff and Student Publications

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we …

Does Receiving A Sars-Cov-2 Antibody Test Result Change Covid-19 Protective Behaviors? Testing Risk Compensation In Undergraduate Students With A Randomized Controlled Trial, Christina Ludema, Molly S Rosenberg, Jonathan T Macy, Sina Kianersi, Maya Luetke, Chen Chen, Lilian Golzarri-Arroyo, Erin Ables, Kevin Maki, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: Risk compensation, or matching behavior to a perceived level of acceptable risk, can blunt the effectiveness of public health interventions. One area of possible risk compensation during the SARS-CoV-2 pandemic is antibody testing. While antibody tests are imperfect measures of immunity, results may influence risk perception and individual preventive actions. We conducted a randomized control trial to assess whether receiving antibody test results changed SARS-CoV-2 protective behaviors.

Purpose: Assess whether objective information about antibody status, particularly for those who are antibody negative and likely still susceptible to SARS-CoV-2 infection, increases protective behaviors. Secondarily, assess whether a positive antibody test …

Cardiac Physical Exam Skills And Auscultation Session For Pediatric Interns, Christopher A Sumski, Anoop Singh, Amanda Rogers, Robert Treat, Charles Bergstrom

2020-Current year OA Pubs

INTRODUCTION: Physicians need adequate physical exam skills. Unfortunately, interns have variable physical exam skills, and teaching is often limited to rounds, an inconsistent setting. Physical exam skills, particularly those involving auscultation, require practice. Our goal was to create a cardiac physical exam workshop for pediatric interns that would improve their performance on an interactive assessment of their ability and understanding in physical exam and murmur interpretation.

METHODS: We completed a targeted needs assessment and then developed a 2-hour workshop on the pediatric cardiac physical exam targeted to pediatrics residents. The workshop included didactics, group discussion, and practice interpreting common pediatric …

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance In Cantu Syndrome, Gautam K Singh, Conor Mcclenaghan, Manish Aggarwal, Hongjie Gu, Maria S Remedi, Dorothy K Grange, Colin G Nichols

2020-Current year OA Pubs

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in

In-Depth Analysis Of Alternative Splicing Landscape In Multiple Myeloma And Potential Role Of Dysregulated Splicing Factors, Sanika Derebail, Philippe Moreau, Kenneth C Anderson, Giovanni Parmigiani, Mehmet K Samur, Nikhil C Munshi

Faculty, Staff and Student Publications

Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we …

Stabilization Of Mcl-1 By E3 Ligase Traf4 Confers Radioresistance, Yu Gan, Shuangze Han, Xinfang Yu, Haidan Liu, Wei Li

Faculty, Staff and Students Publications

The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of …

Integrated Multi-Omic Analysis Of Low-Grade Ovarian Serous Carcinoma Collected From Short And Long-Term Survivors, Kwong-Kwok Wong, Nicholas W Bateman, Chun Wai Ng, Yvonne T M Tsang, Charlotte S Sun, Tri V Nguyen, R Tyler Hillman, Jianhua Zhang, P Andrew Futreal, Christine Rojas, Kelly A Conrads, Brian L Hood, Clifton L Dalgard, Matthew D Wilkerson, Neil T Phippen, Thomas P Conrads, George L Maxwell, Anil K Sood, David M Gershenson

Faculty, Staff and Student Publications

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors.

METHODS: Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. …

A Systematic Approach To Provide Feedback To Presenters At Virtual And Face-To-Face Professional Meetings, S Beth Bierer, Anna Cianciolo, Heeyoung Han, Janice Hanson

2020-Current year OA Pubs

INTRODUCTION: To promote their personal and professional growth, medical educators need practical, actionable feedback on their scholarship, as well as guidance for documenting their scholarship in educator portfolios. We offer a framework and resources to provide formative and summative feedback to faculty, administrators, and/or learners delivering an oral presentation at a face-to-face or virtual health professions education meeting.

METHODS: In 2014, the leadership of the Central Group on Educational Affairs (CGEA) meeting planning committee developed and piloted a process to provide individuals with formative and summative feedback on their oral CGEA research presentations at face-to-face meetings and create a transparent …

Processing And Cryopreservation Of Human Ureter Tissues For Single-Cell And Spatial Transcriptomics Assays, Emily E Fink, Surbhi Sona, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Characterizing the cellular heterogeneity of human ureter tissues using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics provides a detailed atlas of cell types, signaling networks, and potential cell-cell cross talk underlying developmental and regenerative pathways. We describe an optimized protocol for generating, cryopreserving, and thawing single-cell suspensions from ureter tissues isolated post-cystectomy for scRNA-seq. In addition, we describe an optimized protocol for cryopreserving human ureter tissues for 10x Genomics Visium spatial gene expression platform. For complete details on the use and execution of this protocol, please refer to Fink et al. (2022).

In Vivo Characterization Of Glutamine Metabolism Identifies Therapeutic Targets In Clear Cell Renal Cell Carcinoma, Akash K Kaushik, Amy Tarangelo, Lindsey K Boroughs, Mukundan Ragavan, Yuanyuan Zhang, Xiangyi Li, Jui-Chung Chiang, Vanina T Tcheuyap, Faeze Saatchi, Quyen N Do, Cissy Yong, Tracy Rosales, Christina Stevens, Aparna D Rao, Brandon Faubert, Panayotis Pachnis, Lauren G Zacharias, Hieu Vu, Feng Cai, Thomas P Mathews, Giannicola Genovese, Barbara S Slusher, Payal Kapur, Xiankai Sun, Matthew Merritt, James Brugarolas, Ralph J Deberardinis

Faculty, Staff and Student Publications

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with …

Neuromotor Changes In Participants With A Concussion History Can Be Detected With A Custom Smartphone App, Christopher K. Rhea, Masahiro Yamada, Nikita A. Kuznetsov, Jason T. Jakiela, Chanel T. Lojacono, Scott E. Ross, F. J. Haran, Jason M. Bailie, W. Geoffrey Wright

Moss-Magee Rehabilitation Papers

Neuromotor dysfunction after a concussion is common, but balance tests used to assess neuromotor dysfunction are typically subjective. Current objective balance tests are either cost- or space-prohibitive, or utilize a static balance protocol, which may mask neuromotor dysfunction due to the simplicity of the task. To address this gap, our team developed an Android-based smartphone app (portable and cost-effective) that uses the sensors in the device (objective) to record movement profiles during a stepping-in-place task (dynamic movement). The purpose of this study was to examine the extent to which our custom smartphone app and protocol could discriminate neuromotor behavior between …

Social Attention During Object Engagement: Toward A Cross-Species Measure Of Preferential Social Orienting, Claire Weichselbaum, Nicole Hendrix, Jordan Albright, Joseph D Dougherty, Kelly N Botteron, John N Constantino, Natasha Marrus

2020-Current year OA Pubs

BACKGROUND: A central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD.

METHODS: Play behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples …

Tissue Registration And Exploration User Interfaces In Support Of A Human Reference Atlas, Katy Börner, Andreas Bueckle, Bruce W Herr 2nd, Leonard E Cross, Ellen M Quardokus, Elizabeth G Record, Yingnan Ju, Jonathan C Silverstein, Kristen M Browne, Sanjay Jain, Clive H Wasserfall, Marda L Jorgensen, Jeffrey M Spraggins, N Heath Patterson, Griffin M Weber

2020-Current year OA Pubs

Seventeen international consortia are collaborating on a human reference atlas (HRA), a comprehensive, high-resolution, three-dimensional atlas of all the cells in the healthy human body. Laboratories around the world are collecting tissue specimens from donors varying in sex, age, ethnicity, and body mass index. However, harmonizing tissue data across 25 organs and more than 15 bulk and spatial single-cell assay types poses challenges. Here, we present software tools and user interfaces developed to spatially and semantically annotate ("register") and explore the tissue data and the evolving HRA. A key part of these tools is a common coordinate framework, providing standard …

Consensus Opinion From An International Group Of Experts On Measurable Residual Disease In Hairy Cell Leukemia, Farhad Ravandi, Robert J Kreitman, Enrico Tiacci, Leslie Andritsos, Versha Banerji, Seema A Bhat, Alessandro Broccoli, Timothy Call, Dai Chihara, Claire Dearden, Judit Demeter, Sasha Dietrich, Monica Else, Narendranath Epperla, Brunangelo Falini, Francesco Forconi, Douglas E Gladstone, Alessandro Gozzetti, Sunil Iyengar, James B Johnston, Jeffrey Jorgensen, Gunnar Juliusson, Francesco Lauria, Gerard Lozanski, Sameer A Parikh, Jae H Park, Aaron Polliack, Graeme Quest, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Philip A Thompson, Xavier Troussard, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani, Bernhard Wörmann, Kanti Rai, Michael Grever

Faculty, Staff and Student Publications

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the …

Histopathological Tumour Response Scoring In Resected Pancreatic Cancer Following Neoadjuvant Therapy: International Interobserver Study (Isgpp-1), Boris V Janssen, Stijn Van Roessel, Susan Van Dieren, Onno De Boer, Volkan Adsay, Lodewijk Brosens, Deyali Chatterjee, Angela Chou, Claudio Doglioni, Irene Esposito, Roger Feakins, Talia L Fuchs, Noriyoshi Fukushima, Anthony J Gill, Seung-Mo Hong, Ralph H Hruban, Jeffrey Kaplan, Alyssa Krasinkas, Claudio Luchini, Chanjuan Shi, Aatur Singhi, Elizabeth Thompson, Marie-Louise F Velthuysen, Marc G Besselink, Joanne Verheij, Huamin Wang, Caroline Verbeke, Arantza Fariña

Faculty, Staff and Student Publications

Background: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems.

Methods: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The …

Mendelian Randomization And Genetic Colocalization Infer The Effects Of The Multi-Tissue Proteome On 211 Complex Disease-Related Phenotypes, Chengran Yang, Anne M Fagan, Richard J Perrin, Herve Rhinn, Oscar Harari, Carlos Cruchaga

2020-Current year OA Pubs

BACKGROUND: Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes.

METHODS: Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several …

Trib3 Mediates Fibroblast Activation And Fibrosis Though Interaction With Atf4 In Ipf, Zhongzheng Li, Weiming Zhao, Kai Xu, Ningdan Wang, Hui Lian, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM …

Contributions Of Semantic And Phonological Working Memory To Narrative Language Independent Of Single Word Production: Evidence From Acute Stroke

Faculty, Staff and Student Publications

Neuropsychological case studies have provided evidence that individuals with semantic, but not phonological, working memory (WM) deficits have difficulty producing phrases containing several content words. These findings supported the claim of a phrasal scope of planning at the grammatical formulation stage of production, where semantic WM supports the maintenance of lexical-semantic representations as they are inserted into slots in phrasal constituents. Recent narrative production results for individuals at the acute stage of stroke supported the role for semantic WM in phrasal elaboration while suggesting a role for phonological WM at a subsequent phonological encoding stage in supporting fluent, rapid speech. …

Defective Proteostasis In Induced Pluripotent Stem Cell Models Of Frontotemporal Lobar Degeneration, Sidhartha Mahali, Rita Martinez, Melvin King, Anthony Verbeck, Oscar Harari, Bruno A Benitez, Kanta Horie, Chihiro Sato, Sally Temple, Celeste M Karch

2020-Current year OA Pubs

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We …

G-Rich Motifs Within Phosphorothioate-Based Antisense Oligonucleotides (Asos) Drive Activation Of Fxn Expression Through Indirect Effects, Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Pranathi Meda Krishnamurthy, Michael R Green, Athma A Pai, Jonathan K Watts

Faculty, Staff and Student Publications

Friedreich's ataxia is an incurable disease caused by frataxin (FXN) protein deficiency, which is mostly induced by GAA repeat expansion in intron 1 of the FXN gene. Here, we identified antisense oligonucleotides (ASOs), complementary to two regions within the first intron of FXN pre-mRNA, which could increase FXN mRNA by ∼2-fold in patient fibroblasts. The increase in FXN mRNA was confirmed by the identification of multiple overlapping FXN-activating ASOs at each region, two independent RNA quantification assays, and normalization by multiple housekeeping genes. Experiments on cells with the ASO-binding sites deleted indicate that the ASO-induced FXN activation was driven by …

Methylprednisolone For Heart Surgery In Infants - A Randomized, Controlled Trial, Kevin D Hill, Pirooz Eghtesady, Et Al.

2020-Current year OA Pubs

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown.

METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes.

RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for …